With Formic Acid

4-amino- l-methylimidazole-5-carboxamide (see 18) gave a good yield of 9-methylpurin-6-one (see 19) when refluxed with these reagents for 2 hr,201 and 4-aminoimidazole-5-carboxamide required only 30 min at 70°C.202 In the more 7i-deficient pyrazine series, 2 hr of boiling with the 

Alkaline closures are also possible. 2-Formamido-6-methylpyrazine-3-(JV-methyl)carboxamide gave a good yield of 3,7-dimethylpteridin-4-one when boiled in 0.5 N sodium bicarbonate for 5 min.206 For the less 7r-deficient 4-formamidoimidazole-5-carboxamide, 0.05 N sodium bicarbonate sufficed to produce an excellent yield of hypoxanthine (purin-6-one).204 These alkaline conditions are well tolerated by glycosides. 

When more powerful cyclizing reagents are required, the use of formamide and particularly ortho esters, especially when acid-catalyzed, can be recommended (see Sections 3 and 4 below). 

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In some instances the use of sulphuric acid leads to unsatisfactory results. Thus with formic acid carbon monoxide would be evolved. Esters of formic acid are most simply prepared from the alcohol and excess of formic acid, for example ... 

Allyl alcohol may be prepared by heating glycerol with formic acid ... 

The alkenylpalladium intermediate 364, formed by the intramolecular insertion of 363, is terminated by hydrogenolysis with formic acid to give the terminal alkene 365[266]. The intramolecular insertion of 366 is terminated by the reaction of the alkynylstannane 367 to afford the conjugated dienyne system 368[267j. 

Many examples of insertions of internal alkynes are known. Internal alkynes react with aryl halides in the presence of formate to afford the trisubstituted alkenes[271,272]. In the reaction of the terminal alkyne 388 with two molecules of iodobenzene. the first step is the formation of the phenylacetylene 389. Then the internal alkyne bond, thus produced, inserts into the phenyl-Pd bond to give 390. Finally, hydrogenolysis with formic acid yields the trisubstituted alkene 391(273,274], This sequence of reactions is a good preparative method for trisubstituted alkenes from terminal alkynes. 

Formate is an excellent hydride source for the hydrogenolysis of aryl halides[682]. Ammonium or triethylammonium formate[683] and sodium formate are mostly used[684,685]. Dechlorination of the chloroarene 806 is carried out with ammonium formate using Pd charcoal as a catalyst[686]. By the treatment of 2,4,6-trichloroamline with formate, the chlorine atom at the /iiara-position is preferentially removed[687]. The dehalogenation of 2,4-diha-loestrogene is achieved with formic acid, KI, and ascorbic acid[688]. 

The enone 807 is converted into the dienol triflatc 808 and then the conjugated diene 809 by the hydrogenolysis with tributylammonium for-mate[689,690]. Naphthol can be converted into naphthalene by the hydrogenolysis of its triflate 810[691-693] or sulfonates using dppp or dppf as a ligand[694]. Aryl tetrazoyl ether 811 is cleaved with formic acid using Pd on carbon as a catalyst[695]. 

Asymmetric hydrogenolysis of allylic esters with formic acid with satisfactory ee was observed[387], Geranyl methyl carbonate (594) was reduced to 570 with formic acid using l,8-bis(dimethylamino)naphthalene as a base and MOP-Phen as the best chiral ligand, achieving 85% ee. 

The protected nucleoside-3-phosphoramidite monomer units such as 671 are used in the solid-phase oligonucleotide synthesis. In the 60mer synthesis, 104 allylic protective groups are removed in almost 100% overall yield by the single Pd-catalyze reaction with formic acid and BuNH2[432], N,(9-protection of uridine derivatives was carried out under pha.se-transfer conditions[433]. 

Hydrogenolysis of the diallyl alkylmalonate 757 with formic acid in boiling dioxane affords the monocarboxylic acid 758. Allyl ethyl malonates are converted into ethyl carboxylates[471]. The malonic allyl ester TV-allylimide 759 undergoes smooth deallylation in refluxing dioxane to give the simple imide 760(472]. The allyl cyanoacetate 761 undergoes smooth decarboxylation to give... 

The 2,3-alkadienyl acetate 851 reacts with terminal alkynes to give the 2-alkynyl-1,3-diene derivative 852 without using Cul and a base. In the absence of other reactants, the terminal alkyne 853 is formed by an unusual elimination as an intermediate, which reacts further with 851 to give the dimer 854. Hydrogenolysis of 851 with formic acid affords the 2, 4-diene 855[524]. 

Addition of a hydroxy group to alkynes to form enol ethers is possible with Pd(II). Enol ether formation and its hydrolysis mean the hydration of alkynes to ketones. The 5-hydroxyalkyne 249 was converted into the cyclic enol ether 250[124], Stereoselective enol ether formation was applied to the synthesis of prostacyclin[131]. Treatment of the 4-alkynol 251 with a stoichiometric amount of PdCl2, followed by hydrogenolysis with formic acid, gives the cyclic enol ether 253. Alkoxypalladation to give 252 is trans addition, because the Z E ratio of the alkene 253 was 33 1. 

Formic acid is a good reducing agent in the presence of Pd on carbon as a catalyst. Aromatic nitro compounds are reduced to aniline with formic acid[100]. Selective reduction of one nitro group in 2,4-dinitrotoluene (112) with triethylammonium formate is possible[101]. o-Nitroacetophenone (113) is first reduced to o-aminoacetophenone, then to o-ethylaniline when an excess of formate is used[102]. Ammonium and potassium formate are also used for the reduction of aliphatic and aromatic nitro compounds. Pd on carbon is a good catalyst[103,104]. NaBH4 is also used for the Pd-catalyzed reduction of nitro compounds 105]. However, the ,/)-unsaturated nitroalkene 114 is partially reduced to the oxime 115 with ammonium formate[106]... 

The heterocyclic rings in quinoline (116) and isoquinoline are selectively reduced by Pd on carbon-catalyzed reaction of ammonium formatc[107]. Some benzene rings are also reduced. For example, nitrobenzene is reduced to cyclohexylamine (117) with formic acid. It is important to use a sevenfold excess of formic acid[108]. 

Takatori (274) formylated 2-amino-4-methylthiazole with formic acid. When NHj is bubbled for 6 hr into a mixture of 2-amino-4-methyl-thiazole and propionic acid at 100°C, 2-propionamido-4-methylthiazole is obtained (275). 

Heating 5-amino-4-mercapto pyrimidines (61) with formic acid affords the corresponding thiazolo[5,4d]pyrimidines (62) (Scheme 28) (357, 382, 411, 431). 

Although acetic acid and water are not beheved to form an azeotrope, acetic acid is hard to separate from aqueous mixtures. Because a number of common hydrocarbons such as heptane or isooctane form azeotropes with formic acid, one of these hydrocarbons can be added to the reactor oxidate permitting separation of formic acid. Water is decanted in a separator from the condensate. Much greater quantities of formic acid are produced from naphtha than from butane, hence formic acid recovery is more extensive in such plants. Through judicious recycling of the less desirable oxygenates, nearly all major impurities can be oxidized to acetic acid. Final acetic acid purification follows much the same treatments as are used in acetaldehyde oxidation. Acid quahty equivalent to the best analytical grade can be produced in tank car quantities without difficulties. 

Intermediate formation of formyl chloride is not necessary since the actual alkylating agent, HCO", can be produced by protonation of carbon monoxide or its complexes. However, it is difficult to obtain an equimolar mixture of anhydrous hydrogen chloride and carbon monoxide. Suitable laboratory preparations involve the reaction of chlorosulfonic acid with formic acid or the reaction of ben2oyl chloride with formic acid ... 

Olefins are carbonylated in concentrated sulfuric acid at moderate temperatures (0—40°C) and low pressures with formic acid, which serves as the source of carbon monoxide (Koch-Haaf reaction) (187). Liquid hydrogen fluoride, preferably in the presence of boron trifluoride, is an equally good catalyst and solvent system (see Carboxylic acids). 

Reaction of 1-pentanol with propionic acid provides 1-pentyl propionate [624-54-4] a new coatings solvent for automotive refinish and OEM paints, apphances, and for higher-solids systems (37). The esterification of 1-pentanol with formic acid to 1-pentyl formate [638-49-3] is conducted by concomitant removal of by-product water by a2eotropic distillation with diethyl ether (38). 

Uses ndReactions. Dihydromyrcene is used primarily for manufacture of dihydromyrcenol (25), but there are no known uses for the pseudocitroneUene. Dihydromyrcene can be catalyticaUy hydrated to dihydromyrcenol by a variety of methods (103). Reaction takes place at the more reactive tri-substituted double bond. Reaction of dihydromyrcene with formic acid gives a mixture of the alcohol and the formate ester and hydrolysis of the mixture with base yields dihydromyrcenol (104). The mixture of the alcohol and its formate ester is also a commercially avaUable product known as Dimyrcetol. Sulfuric acid is reported to have advantages over formic acid and hydrogen chloride in that it is less compUcated and gives a higher yield of dihydromyrcenol (105). 

When dihydromyrcene is treated with formic acid at higher temperatures (50°C) than that required to produce dihydromyrcenol and its formate, an unexpected rearrangement occurs to produce a,3,3-trimethylcyclohexane methanol and its formate (106). The product is formed by cyclization of dihydromyrcene to the cycloheptyl carbonium ion, which rearranges to give the more stable cyclohexyl compound (107). The formate ester, a,3,3-trimethylcyclohexane methanol formate [25225-08-5] (57) is a commercially avaUable product known as Aphermate. 

In eadier Hterature carbonochloridic esters are referred to as chloroformates or chlorocarbonates because of the stmctural parallel with formic acid [64-18-6]., chloroformic acid, and carbonic acid. Before 1972, chloroformates were indexed in Chemicaly4bstracts, Eighth Collective Index, under formic acid, chloroesters whereas, in the Ninth Collective Index (Dec. 1990), they are referred to as carbonochloridic acid esters. Table 1 fists the common names of carbonochloridates or chloroformates, the CAS Registry Numbers, and the formulas. 

Hydrazinopyridazines are easily formylated with formic acid or ethyl formate and acety-lated with acetic anhydride. A-Pyridazinylthiosemicarbazides are obtained from thiocyanates or alkyl- and aryl-isothiocyanates. Hydrazinopyridazines condense with aliphatic and aromatic aldehydes and ketones to give hydrazones. 

The anticonvulsant primidone (1035) resembles phenobarbital but lacks the 2-oxo substituent. It was introduced in 1952 and has remained a valuable drug for controlling grand mal and psychomotor epilepsy. As might be expected, primidone is metabolized to yield phenobarbital (1034 X = 0) and C-ethyl-C-phenylmalondiamide (1036), both of which have marked anticonvulsant properties however, primidone does have intrinsic activity and an appropriate mixture of its metabolites has only a fraction of its activity (73MI21303). Primidone may be made in several ways, of which desulfurization by Raney nickel of the 2-thiobarbiturate (1034 X = S) or treatment of the diamide (1036) with formic acid (at 190 °C) seem to be the most satisfactory (54JCS3263). 

Reduced derivatives are obtained from o-aminomethylpyridinamines, e.g. (190) - (191) (58MIP21500), whilst the 3-oxadiazolopyridine (192) undergoes ring opening and reclosure to (193) with formic acid (78JOC393). 

A similar utilization of two heteroatoms is illustrated by the reaction of the ethylenedithiol (120) with formic acid in the presence of perchloric acid. 4,5-Diphenyl-l,3-dithiolylium perchlorate (121) was formed in 45% yield (69MI40300). Introduction of a 2-oxo or 2-thioxo substituent as in (123 X = 0, S) is illustrated by the reaction of the disodium salt (122) with phosgene and thiophosgene, respectively (76S489). 

FIG. 13-65 Valeric acid-water separation with formic acid, (a) Mass balances on distillation region diagram, (h) Conceptual sequence. 

This group was developed for protection of the 5 -OH group in nucleosides. The derivative is prepared from the corresponding triaiylmethyl chloride, and is cleaved by reductive cleavage (Zn/AcOH) of the phenacyl ether to the p-hydroxyphenyl-diphenylmethyl ether followed by acidic hydrolysis with formic acid. ... 

If aminoguanidine sulfate is available, the first part of this preparation may be omitted and 61.5 g. of the sulfate treated with formic acid as directed in the second paragraph. 

FIGURE 8.6 Comparison of hexafluoro-2-propanol (HFIP) with formic acid as a denaturing agent in SEC. Eiution positions of neutral amino acids were similar with both agents. The elution positions of Lys and Asp shifted dramatically in C, as shown by the tie lines, but this was an effect of pH (see Fig. 8.7). The elution positions of a-MSH and formic acid are shown to demonstrate that the amino acids eluted within Vo and V,. Column Same as Fig. 8.1. Flow rate 1.0 ml/min. Mobile phase As noted. Detection Aiij = 0.1 AUFS. 

H. Reaction with Formic and Trichloroacetic Acids Enamines derived from aldehydes have been treated with formic acid under the conditions of the Leuckart-Wallach reaction 141) to give saturated tertiary amines 142). The enamine (98) reacts vigorously with formic acid at room temperature to give N-isobutyl morpholine (204). 

The reduction of the double bond of an enamine is normally carried out either by catalytic hydrogenation (MS) or by reduction with formic acid (see Section V.H) or sodium borohydride 146,147), both of which involve initial protonation to form the iminium ion followed by hydride addition. Lithium aluminum hydride reduces iminium salts (see Chapter 5), but it does not react with free enamines except when unusual enamines are involved 148). 

The remaining major method for the reduction of the C=N+ functionality is the reaction with formic acid. The first report was that of Luke , who found (95) that thermal cleavage of l,l-dimethyl-2-methylenepyrrolidinium formate was accompanied by reduction. Lukes then explored the generality... 

That the reduction with formic acid proceeds by a hydride transfer reaction was proposed by Lukes and Ji2ba 100) and finally proven by Leonard and Sauers 63). The use of variously deuterated formic acid allowed Leonard and Sauers to determine that (1) protonation or... 

Reduction of Iminium Salts with Formic Acid (96-99)... 

An interesting addition of ethyl acrylate has been reported in the case of l-methyl-2-ethylidenepyrrolidine. An unsaturated amino ketone 144 is formed, which rearranges to 1,7-dimethyloctahydroindole (145) on reduction with formic acid, as established by dehydrogenation to 1,7-dimethyl-indole (Scheme 12) 217). 

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